James Archibald Mixson, M.D. Assistant Professor of Pathology
Department:
Pathology
UMGCC Research Program:
Hormone Responsive Cancers Program
Education/Training:
College Degree:
B.A., Vanderbilt University
Medical Degree:
M.D., Emory University
Residency:
Internal Medicine, Emory University
Fellowship:
National Institutes of Health
Certification:
Internal Medicine, Maryland; #D0035064
Contact
Information:
Mailing Address:
Univeristy of Maryland School of Medicine
Bldg. MSTF, Rm. 7-59
10 South Pine Street
Baltimore, MD 21201
Email:
amixson@umaryland.edu
Phone:
301-706-3223
Fax:
301-706-8414
Research Interests:
The tumor vasculature is an increasingly important target of gene therapy. Nevertheless, non-viral delivery systems including cationic liposomes require marked improvement to enable effective targeting of the tumor vasculature. Our laboratory is interested in developing novel non-viral carriers of antiangiogenic nucleic acids (antisense oligonucleotides, siRNA, and genes).
We have developed branched peptides comprised of histidine and lysine that are efficient carriers of nucleic acids for both in vitro and in vivo. The branched co-peptide is composed of lysine and histidine; the lysine component forms a complex with and partially neutralizes the negative charge of the plasmid DNA, and the histidine component with a pKa of approximately 6.0, buffers and aids in the release of plasmid DNA from endosomal vesicles.
To determine the mechanisms that further our understanding of H-K polymers as nucleic acid carriers, we are examining the interplay between affinities of HK polymers, DNA, and the cells endosomal pH. It is anticipated that these mechanistic studies will lead to improvement of the HK carriers and have implications for improvement of gene therapy. To date, our HK polymers in complex with marker genes such as luciferase localize in tumors when administered intravenously in mouse models. With further development of the H-K carrier, we plan on coupling the most effective "antiangiogenic gene" and non-viral carrier to inhibit more effectively tumor growth in a mouse model.
Publications:
Lesoon-Wood, L., Kim, W.H., Kleinman, H., Weintraub, B., and Mixson, A.J.: Systemic gene therapy with p53 interferes with progression of breast cancer in nude mice. Human Gene Therapy, 1995, 6, 395-405.
Xu, M., Kumar, D., Srinivas, S., DeTolla, L.T., Yu, S.F., Stass, S.A., and Mixson, A.J.: Parenteral gene therapy with p53 inhibits human breast tumors in vivo through a bystander mechanism without evidence of toxicity. Human Gene Therapy, 1997, 8, 177-185.
Chen, Q.R., Kumar, Stass, S.A., and Mixson, A.J.: Liposomes complexed to angiostatin and endostatin inhibit breast cancer in nude mice. Cancer Research, 1999, 59, 3308-12.
Chen, Q.R., Zhang, L., Stass, S.A., and Mixson, A.J.: Branched co-polymers of histidine and lysine are efficient carriers of plasmids. Nucleic Acids Research, 2001, 29, 1334-40.
Chen, Q.R., Zhang, L., Luther, P.W., and Mixson, A.J.: Optimal transfection with the HK polymer depends on its degree of branching and the pH of endocytic vesicles. Nucleic Acids Research, 2002, 30, 1338-1345.
Zhang, L., Gasper, W.J.,Stass, S.A., Ioffe, O.B., Davis, M.A., and Mixson, A.J. : Angiogenic Inhibition Mediated by a DNAzyme That Targets Vascular Endothelial Cell Growth Factor Receptor 2. Cancer Research, 2002, 62, 5463-5469.
Leng, Q. and Mixson, A.J.: Highly branched HK peptides are effective carriers of siRNA. The Journal of Gene Medicine. In Press, 2005
